US12275685B2 - Oligo-benzamide analogs and their use in cancer treatment - Google Patents

Oligo-benzamide analogs and their use in cancer treatment Download PDF

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US12275685B2
US12275685B2 US17/337,830 US202117337830A US12275685B2 US 12275685 B2 US12275685 B2 US 12275685B2 US 202117337830 A US202117337830 A US 202117337830A US 12275685 B2 US12275685 B2 US 12275685B2
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Ganesh RAJ
Jung-Mo Ahn
Ratna K. Vadlamudi
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University of Texas System
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present disclosure relates in general to the field of peptidomimetics and specifically to compositions of matter and methods of their use in medical indications, such as cancer.
  • Peptidomimetics are small organic molecules that do not possess the peptide backbone structure, however, still retain a capability to interact with the same target protein by arranging essential functional groups (i.e., pharmacophores) in a required three-dimensional pattern complimentary to a binding pocket in the protein. Since peptides and proteins adopt and utilize secondary structures (e.g., ⁇ -helix, ⁇ -sheet, and reverse turns) to make their global shapes and to recognize their binding partners, rational design of secondary structure mimetics is an important strategy in developing small molecule modulators for protein complex formation, compared to conventional high-throughput screening of a chemical library.
  • essential functional groups i.e., pharmacophores
  • the present disclosure provides oligo-benzamide peptidomimetic compounds for use in the treatment and/or prevention of cancer. These small molecules include ⁇ -helix mimetics that represent helical segments in the target molecules.
  • the oligo-benzamide peptidomimetic compounds modulate protein-protein, protein-peptide, or protein-drug interaction to exert a variety of physiological consequences.
  • the oligo-benzamide peptidomimetic compounds also cause significant endoplasmic reticulum stress in cancer cells and may effectively shut down de novo protein synthesis, leading to cell death.
  • the present disclosure provides compounds of the formula:
  • the compounds are of formula (I). In further embodiments, the compounds are further defined as:
  • the compounds are further defined as:
  • the compounds are further defined as:
  • R 9 is aralkyl (C ⁇ 18) or substituted aralkyl (C ⁇ 18) . In further embodiments, R 9 is aralkyl (C ⁇ 18) , such as 2-(naphthalen-2-yl)ethyl.
  • R 6 is amido (C ⁇ 12) or substituted amido (C ⁇ 12) . In further embodiments, R 6 is substituted amido (C ⁇ 12) , such as 3-aminopropanamido.
  • the compound is further defined as:
  • the compound is further defined as:
  • the compound is further defined as:
  • compositions comprising:
  • the composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.
  • the composition is formulated for administration: orally, intraarterially, intratumorally,
  • the present disclosure provides methods of treating a disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.
  • the patient is a mammal, such as a human.
  • the disease or disorder is cancer.
  • the cancer is a therapy resistant cancer.
  • the cancer is breast cancer, ovarian cancer, pancreatic cancer, or brain cancer.
  • the cancer is breast cancer, such as triple negative breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is pancreatic cancer.
  • the cancer is brain cancer, such as glioblastoma.
  • the cancer is an estrogen receptor-positive cancer.
  • the cancer is an estrogen receptor-negative cancer.
  • administering comprises intravenous, intra-arterial, intra-tumoral, subcutaneous, topical or intraperitoneal administration. In some embodiments, administering comprises local, regional, systemic, or continual administration. In some embodiments, the methods further comprise providing to said subject a second anti-cancer therapy. In some embodiments, said second anti-cancer therapy is surgery, chemotherapy, radiotherapy, hormonal therapy, toxin therapy, immunotherapy, and cryotherapy. In some embodiments, said second anti-cancer therapy is provided prior to administering said compound. In other embodiments, said second anti-cancer therapy is provided after administering said compound. In still other embodiments, said second anti-cancer therapy is provided at the same time as said compound.
  • said compound is administered daily. In some embodiments, said compound is administered daily for 7 days, 2 weeks, 3 weeks, 4 weeks, one month, 6 weeks, 8 weeks, two months, 12 weeks, or 3 months. In further embodiments, said compound is administered weekly. In some embodiments, said compound is administered weekly for 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks. In some embodiments, the compound or composition is administered in an amount sufficient to induce endoplasmic reticulum stress and/or shut down protein synthesis. In some embodiments, said compound acts via inducing endoplasmic reticulum stress within hours of administration and subsequently shuts down protein synthesis. In some embodiments, the level of basal endoplasmic reticulum stress or the compensatory unfolded protein response within a cell dictates the response to the drug.
  • FIG. 1 shows primary TK41 (i.e., ERX-41) structure and low energy helical conformation.
  • FIGS. 2 A- 2 C show the potency of TK41 (IC 50 from 50-500 nM) on estrogen receptor-positive ( FIG. 2 A ), estrogen receptor-negative ( FIG. 2 B ) and therapy resistant ERMT ( FIG. 2 C ) cells determined by MTT assay.
  • FIGS. 3 A- 3 C show TK41 (i.e., ERX-41) docked on TLX (MacroModel and AutoDock; FIG. 3 A ). Interaction with purified TLX protein was analyzed, following incubation with biotinylated-ERX-41, using avidin bead pull down ( FIG. 3 B ). FIG. 3 C shows GST-TLX was incubated with TNBC cellular lysates in the presence or absence of TK41 (1 ⁇ M) and TLX interaction with PELP1 was analyzed by GST pull down followed by westerns.
  • TK41 i.e., ERX-411
  • FIG. 3 A shows Interaction with purified TLX protein was analyzed, following incubation with biotinylated-ERX-41, using avidin bead pull down ( FIG. 3 B ).
  • FIG. 3 C shows GST-TLX was incubated with TNBC cellular lysates in the presence or absence of TK41 (1 ⁇ M)
  • FIGS. 4 A- 4 C show the effect of TK41 on estrogen receptor-positive (ER+ve) tumor growth.
  • xenografts were established in nude mice and treated with either vehicle (circle markers) or 10 mg/kg/day TK41 (square markers) administered as an oral gavage in Captisol®.
  • Effect on tumor volume is shown in FIG. 4 A .
  • Effect on tumor weight is shown in FIG. 4 B .
  • Comparison of mice body weights is shown in bar graphs ( FIG. 4 C ). *p ⁇ 0.05; **** p ⁇ 0.001.
  • FIGS. 5 A- 5 C show the effect of TK41 on triple negative breast cancer xenograft tumors.
  • xenografts were established in nude mice and treated with either vehicle (circle markers) or 10 mg/kg/day TK41 (square markers) administered as an oral gavage in Captisol®.
  • Comparison of mice body weights is shown in bar graphs ( FIG. 5 A ).
  • Effect on tumor weight is shown in FIG. 5 B .
  • Effect on tumor volume is shown in FIG. 5 C .
  • Photographs of individual tumors at necropsy supports the effect of TK41 on TNBC. *p ⁇ 0.05; **** p ⁇ 0.001.
  • FIGS. 7 A- 7 C show effect of TK41 in triple negative breast cancer in patient derived xenografts.
  • Tumor volume FIG. 7 A
  • distribution of tumor weights at necropsy FIG. 7 B
  • mice body weights bar graph; FIG. 7 C
  • FIG. 7 C support that ERX-41 has activity against TNBC PDX tumors. *p ⁇ 0.05; ****p ⁇ 0.001.
  • FIGS. 8 A & 8 B show the effect of TK41 (i.e., ERX-41) on therapy resistant cancer cells.
  • ERMT therapy resistant
  • Tumor volume FIG. 8 A
  • mice body weights (bar graph; FIG. 8 B ) support that ERX-41 has activity against ERMT tumors. *p ⁇ 0.05; **p ⁇ 0.01.
  • FIG. 9 shows structure activity relationship between TK11 (i.e., ERX-11; Raj et al., 2017), TK41, TK207, TK203, TK208, and YL144.
  • TK11 i.e., ERX-11; Raj et al., 2017
  • TK41 TK207, TK203, TK208, and YL144.
  • Replacement of the R 5 amino group of TK11 with a substituted amino groups significantly increased activity against estrogen receptor-positive and estrogen receptor-negative cells lines.
  • FIGS. 10 A & 10 B show effects of TK208 against cancer cells.
  • FIG. 10 A shows the effect of TK208 against a variety of TNBC cell lines.
  • FIG. 10 B shows the effect of TK208 against a variety of ovarian cancer cell lines.
  • FIGS. 11 A & 11 B show the comparison of cytotoxic effects of TK208 in BT549 NR1H4 knockout cells versus the parental cell.
  • FIG. 11 A shows the results of the cell viability assay.
  • FIG. 11 B shows the results of the caspase assay, demonstrating the effect of TK208 on apoptosis.
  • FIGS. 12 A- 12 D show the effect of TK208 against ovarian cancer cell lines ES2 ( FIGS. 12 A & 12 B ) and SKOV3 ( FIGS. 12 C & 12 D ).
  • FIGS. 12 A & 12 C show TK208 promotes apoptosis both ovarian cancer cells.
  • FIGS. 12 B & 12 D show TK208 reduces cell viability in both cancer cell lines.
  • FIG. 13 shows TK208 reduces colony formation of ES2 and SKOV3 ovarian cancer cells.
  • FIG. 14 shows TK208 reduces invasion of ES2 and SKOV3 ovarian cancer cells.
  • FIG. 15 shows TK208 promotes growth arrest of ES2 and SKOV3 ovarian cancer cells in S phase.
  • FIG. 16 shows the effect of YL144 on breast cancer cells from various cell lines.
  • FIG. 17 shows the effect of YL144 on BT549/NR targeted knockout cells.
  • FIG. 18 shows the effect of YL144 on cell viability of VDR-CRISPR knockout cells.
  • FIG. 19 shows structure activity relationship between TK11 (Raj et al., 2017), TK41, TK208, TK231, YL144, TK227, YL1113, and TK245.
  • FIG. 20 shows TK245 has high specificity for estrogen receptor-positive cells.
  • FIG. 23 shows the effect of TK315 on various cancer cell lines.
  • FIG. 25 shows the ability of TK41 to induce endoplasmic reticulum stress in TNBC MD-MBA-231 cells using electron microscopy. TK41 does not induce endoplasmic reticulum stress in HMEC cells (bottom panel)
  • FIG. 26 shows the ability of TK41 to induce endoplasmic reticulum stress in MD-MBA-231 cell using western blots. TK41 does not induce endoplasmic reticulum stress in HMEC cells.
  • FIG. 29 shows the ability of TK41 to induce endoplasmic reticulum stress in pancreatic cancer MiaPaca cells using electron microscopy. TK41 does not induce endoplasmic reticulum stress in HMEC cells.
  • FIGS. 31 A-D show that oral administration of TK315 (ERX-315) decreased the growth and tumor weight of BC xenografts genetically engineered by CRISPR to express the Y537S ERa mutant in the ZR75 ( FIGS. 31 A-B ) and MCF7 cells ( FIGS. 31 C-D ). No change in body weight was noted.
  • TK315 ERX-315
  • FIGS. 33 A-H show ovarian cancer xenografts (ES2) treated with vehicle or TK208 (ERX-208).
  • Tumor volume FIG. 33 A
  • body weight FIG. 33 B
  • distribution of tumor weights at necropsy FIG. 33 C
  • nodules FIG. 33 D
  • FIGS. 33 E-H show ovarian PDX tumors were treated with vehicle or TK208 (ERX-208).
  • Tumor volume ( FIG. 33 E ) distribution of tumor weights at necropsy ( FIG. 33 F ) and tumor images ( FIG. 33 G ) and body weight ( FIG. 33 H ) were graphed.
  • FIGS. 34 A-C Dose response curve of ERX-41 in multiple TNBC. cell lines using WST-1 assays ( FIG. 34 A ) and CellTiter-Glo assays ( FIG. 34 B ).
  • FIG. 34 C Time lapsed images of live cell imaging with SYTOX Green shows the effect of ERX-41 induced cell death in MDA-MB-231 at 0 h, 20 h and 30 h after treatment with either vehicle or ERX-41. Quantification of the number of dead cells over time seen with live cell imaging in MDAMB-231 and HMEC cells is shown.
  • FIGS. 35 A-P ERX-41 is potent against TNBC in vivo.
  • FIG. 35 A Following establishment of subcutaneous MDA-MB-231 xenograft tumors (200 mm 3 ), 10 mg/kg single dose ERX-41 was administered either by oral or intraperitoneal route. The tumor was harvested 0, 0, 5, 1, 5, 3, 6 and 24 h after drug administration and the drug levels assayed by LC-MS/MS and graphed.
  • FIGS. 35 F-H Tumor volumes were measured using digital calipers and graphed ( FIG. 35 B ). Tumor weights ( FIG. 35 C ), body weights ( FIG. 35 D ) and extirpated tumors (FIG. 35 E) at end of study are also shown.
  • 35 I-P Effect of ERX-41 on the growth ( FIG. 351 , FIG. 35 K , FIG. 35 M , FIG. 35 O ) and tumor weights ( FIG. 35 J , FIG. 35 L , FIG. 35 N , FIG. 35 P ) of four distinct TNBC PDXs compared to vehicle. *p ⁇ 0.05. **p ⁇ 0.01; ***p ⁇ 0.001.
  • FIGS. 36 A-H ERX-41 induces ER stress in TNBC.
  • FIGS. 36 A-C Volcano plots show the relative effect of 4 h treatment of 1 ⁇ M ERX-41 compared to vehicle in MDA-MB-231 ( FIG. 36 A ), BT-549 ( FIG. 36 B ) TNBC and HMEC ( FIG. 36 C ) cell lines.
  • FIG. 36 D Gene ontology analyses show the top regulated pathways.
  • FIG. 36 E Heatmap of the top ER stress and UPR genes in these three TNBC cell lines after 2 h and 4 h treatment with 1 ⁇ M ERX-41 treatment.
  • FIGS. 37 A-J The molecular target of ERX-41 in TNBC is LIPA.
  • FIG. 37 A Visualization of aCRISPR/Cas9 screen in MDA-MB-231 cells shows the genes associated with resistance to ERX-41.
  • FIG. 37 B Knockout clones of LIPA, ACACA, TMEM208, SOAT1 and ARID1A were generated in MDA-MB-231 cells and evaluated for response to ERX-41 using doseresponse curves using CellTiter-Glo assays in vitro.
  • FIGS. 37 C-D Effect of knockout of LIPA in SUM-159 ( FIG. 37 C ) and MDA-MB436 ( FIG.
  • FIGS. 37 E-F Dose response curves of SUM-159 parental cells and clones with LIPA KO to thapsigargin ( FIG. 37 E ) and paclitaxel ( FIG. 37 F ).
  • FIGS. 37 G-H Live cell imaging studies with SYTOX Green to examine ability of 1 ⁇ M ERX-41 to induce cell death in parental SUM-159 and SUM-159 clones with LIPA KO, with quantitation ( FIG. 37 G ) and time-lapsed photomicrographs at 0 h and 30 h (( FIG. 37 H ).
  • FIG. 41 OCa cells were treated with ERX-208 for 16 h and the status of UPR proteins were determined using western blotting.
  • FIG. 43 ES2 and SKOV3 cells were treated with ERX-208 and its effect on cell survival was measured using colony formation assays. ****p ⁇ 0.0001.
  • FIG. 48 A Tumor volume
  • FIG. 48 B tumor weight
  • FIG. 48 C tumors picture
  • FIG. 50 IHC analyses of GRP78, pPERK and Ki67 of ERX-208 treated therapy-resistant HGSOC PDX tumors **p ⁇ 0.01; ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • FIGS. 51 A- 51 C Structure of TX-542 ( FIG. 51 A ) with modeled fit on Y537S MT-ER ⁇ ( FIG. 51 B ) and D538G MT-ER ⁇ ( FIG. 51 C ).
  • FIG. 53 Effect of 100 nM TX-542 on clonogenic survival of WT-ER ⁇ and MT-ER ⁇ BC cell lines.
  • FIG. 54 Effect of 200 nM TX-542, SERMS and SERDs on soft agar colony formation by MCF-7 MT-ER ⁇ Y537S cells.
  • FIG. 55 Effect of 200 nM TX-542 on apoptosis of MT-ER ⁇ expressing BC cells.
  • FIG. 56 Dose-dependent effect of TX-542 on spheroid formation in MCF-7 MT-ER ⁇ Y537S (top) and MCF-7 MT-ER ⁇ D538G (bottom) cells.
  • FIG. 57 Comparative effect of 200 nM tamoxifen, SERDs, fulvestrant and TX-542 on spheroid formation in MCF-7 MT-ER ⁇ Y537S cells.
  • FIG. 58 PK properties of TX-542 indicate a half-life in plasma of 8 h and accumulation over time in tumor.
  • Y-axis shows the relative drug levels in ng/g of tissue.
  • FIG. 60 Effect of 200 nM TX-542 on ER stability in multiple WT-ER ⁇ and MT-ER ⁇ BC cell lines at 24 h.
  • FIGS. 61 A- 61 F Effect of 200 nM TX-542 on the transcriptomic profile in MCF-7 MT-ER ⁇ Y537S cell line after 24 h of treatment.
  • FIG. 61 A Volcano plot shows that 1189 genes were upregulated (log 2FC>0.5, p ⁇ 0.010 and 1029 genes were down regulated (log 2FC ⁇ 0.5, p ⁇ 0.01).
  • GSEA analyses indicate that TX-542 represses the expression of estradiol-induced genes ( FIG. 61 B-C ), induces the expression of estradiol-repressed genes ( FIG. 61 D ) and the expression of apoptotic genes ( FIG. 61 E ).
  • FIG. 62 Effect of TX-542 on invasiveness of BC cells expressing Er ⁇ mutants in a Boyden chamber assay.
  • FIG. 63 Following intracardiac injection of luciferase-tagged ZR-75 MT-ER ⁇ Y537S tumors, mice are imaged five at a time under 2% isoflurane gas anesthesia. Each mouse is injected with D-Luciferin and imaged 10-15 minutes after the injection. BLI signal is quantified in regions of interest (ROIs) drawn around tumors, specific areas (for example cranial, thoracic or abdominal), whole body or tissues ex vivo and the signal is expressed as photons per second, representing the flux radiating omni-directionally from the user-defined region. Images are analyzed using Living Image 4.3.1 (PerkinElmer, Waltham, MA) software.
  • ROIs regions of interest
  • mice were treated either with vehicle or TX-542.
  • Table 3 shows IC 50 of ERX-11 and its analogs ERX-314 and ERX-315 in vitro against MCF-7 and ZR-75 BC cell lines genetically engineered to express either Y537S ERa MT or the D538G ER ⁇ MT.
  • ERX-314 has a methyl group instead of the fluoro group at the N-terminus of ERX-315.
  • FIGS. 66 A-D Effect of ERX-315 on ERa DNA binding on the promoters of 5 canonical ER ⁇ -regulated genes with ERa ChIP in MCF-7 expressing D538G MT-ER ⁇ in the absence and presence of estradiol.
  • FIG. 66 B Heatmap shows the effect of ERX-315 on the transcriptional programme within MCF-7 expressing D538G MT-ER ⁇ , from RNA-sequencing studies.
  • FIG. 66 C Gene ontogeny analyses of the RNA-sequencing studies indicate that estrogen-upregulated genes are downregulated by ERX-315
  • FIG. 66 D Effect of ERX-315 on ER transcriptional activity measured using ERE reporter assay in MCF-7 cells expressing D538G MT-ER ⁇ .
  • FIGS. 67 A- 67 D ERX-315 but not ERX-314 decreases global new protein synthesis at 16 h in MCF-7 expressing mutant D538G but not HMEC cells as shown by western blots for puromycin labeled nascent proteins ( FIG. 67 A ).
  • ERX-315 but not ERX-314 induces uncompensated UPR resulting in LC3B activation ( FIG. 67 B ).
  • ERX-315 decreases expression of ER ⁇ MCF-7 cells with MT-ER ⁇ , both the Y537S and D538G mutants ( FIG. 67 C ), around 12-16 h ( FIG. 67 D ).
  • ERX-315 decease MT-ERa expression and induce ER stress as seen by induction of LC3 for the Y537S and D538G MT-ERa.
  • neither fulvestrant nor GDC-0810 consistently degrade MT-ERa nor induce LC3.
  • FIGS. 68 A- 68 C A) ERX-315 significantly enhances sXBP1 ( FIG. 68 A ) and CHOP ( FIG. 68 B ) mRNA levels and attenuates progesterone receptor (PGR) levels ( FIG. 68 C ) in ZR-75 and MCF-7 cells that express Y537S and D538G MT-ER ⁇ .
  • PGR progesterone receptor
  • FIGS. 70 A- 70 C MCF-7 D538G MT-ERa xenograft tumors shows enhanced peIF2 ⁇ ( FIG. 70 A ), pPERK ( FIG. 70 B ) and CHOP ( FIG. 70 C ) expression 24 h after a single oral 10 mg/kg ERX-315 dose, compared to tumors treated with DMSO.
  • the present disclosure relates oligo-benzamides which are modified with a cyclohexylamide group at the southern terminus of the compound. These compounds have been shown to binding to the hormone receptors in one or more cancer cells such as breast cancer. These compounds may show one or more preferential properties relative to those known in the art, such as improved efficiacy.
  • ERX-41 and ERX-208 have a previously unknown molecular target (LIPA) and mechanism of action (induction of ER stress) and therefore should have utility in treating TNBC and ovarian cancers.
  • LIPA molecular target
  • the expression of LIPA mRNA appears to be highest in renal, breast, pancreatic, ovarian, glioma and lung cancers (Human protein atlas).
  • TK41 (ERX-41) TK314 TK308 TK208 (ERX-208) TK315 (ERX-315) TK309 TK207 TK245 (TX-542) TK227 TK296 YL144 YL1113 YL1116
  • the compounds of the present disclosure are shown, for example, above, in the summary section, and in the claims below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development—A Guide for Organic Chemists (2012), which is incorporated by reference herein.
  • the compounds of the present disclosure have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.
  • a better pharmacokinetic profile e.g., higher oral bioavailability and/or lower clearance
  • Compounds of the present disclosure may contain one or more asymmetrically-substituted carbon or nitrogen atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained.
  • the chiral centers of the compounds of the present disclosure can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.
  • compounds of the present disclosure exist in salt or non-salt form.
  • the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.
  • the symbol “ ” means a single bond where the group attached to the thick end of the wedge is “out of the page.”
  • the symbol “ ” means a single bond where the group attached to the thick end of the wedge is “into the page”.
  • the symbol “ ” means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.
  • variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • a variable is depicted as a “floating group” on a fused ring system, as for example the group “R” in the formula:
  • variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise.
  • Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals —CH—), so long as a stable structure is formed.
  • R may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the minimum number of carbon atoms in the groups “alkyl (C ⁇ 8) ”, “cycloalkanediyl (C ⁇ 8) ”, “heteroaryl (C ⁇ 8) ”, and “acyl (C ⁇ 8) ” is one
  • the minimum number of carbon atoms in the groups “alkenyl (C ⁇ 8) ”, “alkynyl (C ⁇ 8) ”, and “heterocycloalkyl (C ⁇ 8) ” is two
  • the minimum number of carbon atoms in the group “cycloalkyl (C ⁇ 8) ” is three
  • the minimum number of carbon atoms in the groups “aryl (C ⁇ 8) ” and “arenediyl (C ⁇ 8) ” is six.
  • saturated when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below.
  • the term when used to modify an atom, it means that the atom is not part of any double or triple bond.
  • substituted versions of saturated groups one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.
  • saturated when used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.
  • aromatic signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n+2 electrons in a fully conjugated cyclic ⁇ system.
  • An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:
  • Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic ⁇ system, two non-limiting examples of which are shown below:
  • alkylidene groups include: ⁇ CH 2 , ⁇ CH(CH 2 CH 3 ), and ⁇ C(CH 3 ) 2 .
  • An “alkane” refers to the class of compounds having the formula H—R, wherein R is alkyl as this term is defined above.
  • cycloalkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • Non-limiting examples include: —CH(CH 2 ) 2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy).
  • the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure.
  • cycloalkanediyl refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The group
  • cycloalkane refers to the class of compounds having the formula H—R, wherein R is cycloalkyl as this term is defined above.
  • aryl refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present.
  • arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond.
  • alkyl groups carbon number limitation permitting
  • arene refers to the class of compounds having the formula H—R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.
  • aralkyl refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above.
  • Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
  • heteroaryl refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms.
  • heteroarylkyl refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl.
  • acyl refers to the group —C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above.
  • cycloalkylamino refers to groups, defined as —NHR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively.
  • R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively.
  • a non-limiting example of an arylamino group is —NHC 6 H 5 .
  • dicycloalkylamino dialkenylamino”, “dialkynylamino”, “diarylamino”, “diaralkylamino”, “diheteroarylamino”, “diheterocycloalkylamino”, and “dialkoxyamino”, refers to groups, defined as —NRR′, in which R and R′ are both cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively.
  • an “active ingredient” (AI) or active pharmaceutical ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug that is biologically active.
  • Excipient is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles.
  • the main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle.
  • Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life.
  • the suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.
  • IC 50 refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
  • An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
  • a “pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and/or transporting a chemical agent.
  • Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites.
  • Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.
  • a “pharmaceutical drug” (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug, agent, or preparation) is a composition used to diagnose, cure, treat, or prevent disease, which comprises an active pharmaceutical ingredient (API) (defined above) and optionally contains one or more inactive ingredients, which are also referred to as excipients (defined above).
  • API active pharmaceutical ingredient
  • Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
  • Non-limiting examples of suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, and esters of amino acids.
  • a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
  • the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds.
  • a molecule can have multiple stereocenters, giving it many stereoisomers.
  • the total number of hypothetically possible stereoisomers will not exceed 2 n , where n is the number of tetrahedral stereocenters.
  • Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%.
  • enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures.
  • the phrase “substantially free from other stereoisomers” means that the composition contains ⁇ 15%, more preferably ⁇ 10%, even more preferably ⁇ 5%, or most preferably ⁇ 1% of another stereoisomer(s).
  • Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease or symptom thereof in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • unit dose refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration.
  • unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.
  • the present disclosure provides synthetic molecules which present the essential functionalities of corresponding peptide ligands in the proper three dimensional orientation that enables specific protein interactions, leading to either stimulation or inhibition of protein-mediated functions.
  • Peptidomimetics also known as peptide mimetics
  • Peptidomimetics are small organic compounds which lack the peptide backbone of native peptides. Despite this modification, they still retain an ability to interact with corresponding receptors or enzymes by presenting essential chemical functionalities (i.e., pharmacophores) in characteristic three-dimensional patterns which are complimentary to the target proteins (Marshall, 1993; Ahn et al., 2002).
  • essential chemical functionalities i.e., pharmacophores
  • peptidomimetics potentially combine the advantages of peptides (e.g., high efficacy and selectivity, low side effects) and small organic molecules (e.g., high enzymatic stability and oral bioavailability).
  • the present disclosure provides an oligo-benzamide scaffold that is rigid in structure and place and orient substituents as an ⁇ -helix does. Substitution on the rigid tris-benzamide, for instance, allowed easy placement of three functional groups (R 2-4 ) corresponding to the side chains of amino acids found at the i, i+4, and i+7 positions of an ideal ⁇ -helix. Furthermore, the present inventors have developed a facile synthetic route to prepare a number of tris-benzamides to represent ⁇ -helical segments of target proteins.
  • U.S. Patent Publication 2009/0012141 discloses a variety of oligo-benzamide compounds and methods of synthesis therefor.
  • an oligo-benzamide peptidomimetic compound as illustrated includes 2 or 3 optionally substituted benzamides—so called “bis” and “tris” benzamides.
  • linkages between the optionally substituted benzamides may be varied as necessary including ester, thioester, thioamide, trans-ethylene, ethyl, methyloxy, methylamino, hydroxyethyl, carbamate, urea, imide, hydrozido, aminoxy, or other linkages known to the skilled artisan.
  • the oligo-benzamide peptidomimetic compound may be attached to amino acids, oligopeptides, optionally substituted alkyl, or other structures known to the skilled artisan.
  • substitution on the substituted benzamide is generally on a benzene ring and may be on the 2, 3, 4, 5, or 6 position of each of the benzene rings.
  • the substitutions may be at the same position on each of the benzamide rings but may also be at different positions on each of the benzene rings.
  • the substitution is connected to the benzamide ring by a chemical linkage including ether, thioether, amine, amide, carbamate, urea, and carbon-carbon (single-, double-, and triple-) bonds, and the substitution comprises optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl
  • the present disclosure also provides an oligo-benzamide peptidomimetic compound that includes at least two optionally substituted benzamides, with each of the substituted benzamides having one substitution on a benzene ring.
  • the substitutions are individually attached to the benzene rings of the oligo-benzamide peptidomimetic compound by a chemical linkage including ether, thioether, amine, amide, carbamate, urea, and carbon-carbon (single-, double-, and triple-) bonds.
  • substitutions generally include optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, caboxamido groups, carbamoyl groups, carboxyl groups, carbonyl groups, alk
  • U.S. Patent Publication 2009/0012141 provides synthesis schemes to prepare ⁇ -helix mimetic compounds of the present disclosure, for example, in FIG. 2 therein.
  • a specific example in that document provides fifteen ⁇ -helix mimetic compounds made starting with a 4-amino-3-hydroxybenzoic acid compound 7, which was converted to an N—Ac protected methyl ester compound 8.
  • Various alkyl groups were introduced to the hydroxyl group using a variety of alkyl halides and a base (e.g., NaOH) known to the skilled artisan.
  • methyl ester compound 9 was hydrolyzed using a base (like LiOH), and methyl 4-amino-3-hydroxybenzoate compound 10 was coupled to the free benzoic acid using a coupling reagent (like BOP), resulting in a benzamide compound 11 containing one alkyl group corresponding to the i position of a helix.
  • a coupling reagent like BOP
  • formulation comprises admixing or combining one or more of the compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol.
  • the pharmaceutical formulation may be tableted or encapsulated.
  • compositions may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, and intraperitoneal).
  • the compounds disclosed herein may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound.
  • To administer the active compound by other than parenteral administration it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier.
  • the compounds and other ingredients may also be enclosed in a hard or soft-shell gelatin capsule, compressed into tablets, or incorporated directly into the patient's diet.
  • the compounds disclosed herein may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained.
  • the therapeutic compound may also be administered topically to the skin, eye, ear, or mucosal membranes.
  • Administration of the therapeutic compound topically may include formulations of the compounds as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture.
  • the therapeutic compound may be combined with one or more agents that increase the permeability of the compound through the tissue to which it is administered.
  • the topical administration is administered to the eye.
  • Such administration may be applied to the surface of the cornea, conjunctiva, or sclera. Without wishing to be bound by any theory, it is believed that administration to the surface of the eye allows the therapeutic compound to reach the posterior portion of the eye.
  • mice K m of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K m of 12 (given a weight of 3 kg and BSA of 0.24).
  • the actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. These factors may be determined by a skilled artisan.
  • the practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication.
  • the agent(s) may be administered on a routine schedule.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined.
  • the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between.
  • the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
  • the disclosure provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake.
  • the agent can be taken every morning and/or every evening, regardless of when the patient has eaten or will eat.
  • Breast cancer refers to cancers originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas. There are many different types of breast cancer, with different stages (spread), aggressiveness, and genetic makeup; survival varies greatly depending on those factors. Computerized models are available to predict survival. With best treatment and dependent on staging, 10-year disease-free survival varies from 98% to 10%. Treatment includes surgery, drugs (hormonal therapy and chemotherapy), and radiation.
  • breast cancer comprises 10.4% of all cancer incidence among women, making it the second most common type of non-skin cancer (after lung cancer) and the fifth most common cause of cancer death.
  • lung cancer the second most common type of non-skin cancer
  • breast cancer caused 519,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths).
  • Breast cancer is about 100 times more common in women than in men, although males tend to have poorer outcomes due to delays in diagnosis.
  • Some breast cancers require the hormones estrogen and progesterone to grow, and have receptors for those hormones. After surgery those cancers are treated with drugs that interfere with those hormones, usually tamoxifen, and with drugs that shut off the production of estrogen in the ovaries or elsewhere; this may damage the ovaries and end fertility. After surgery, low-risk, hormone-sensitive breast cancers may be treated with hormone therapy and radiation alone. Breast cancers without hormone receptors, or which have spread to the lymph nodes in the armpits, or which express certain genetic characteristics, are higher-risk, and are treated more aggressively.
  • breast cancer is commonly diagnosed using a “triple test” of clinical breast examination (breast examination by a trained medical practitioner), mammography, and fine needle aspiration cytology. Both mammography and clinical breast exam, also used for screening, can indicate an approximate likelihood that a lump is cancer, and may also identify any other lesions.
  • Fine Needle Aspiration and Cytology FNAC
  • FNAC Fine Needle Aspiration and Cytology
  • Clear fluid makes the lump highly unlikely to be cancerous, but bloody fluid may be sent off for inspection under a microscope for cancerous cells. Together, these three tools can be used to diagnose breast cancer with a good degree of accuracy.
  • biopsy Other options for biopsy include core biopsy, where a section of the breast lump is removed, and an excisional biopsy, where the entire lump is removed.
  • vacuum-assisted breast biopsy may help diagnose breast cancer among patients with a mammographically detected breast in women according to a systematic review.
  • ADH atypical ductal hyperplasia
  • DCIS ductal carcinoma in situ
  • Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve an earlier diagnosis. The assumption is that early detection will improve outcomes. A number of screening tests have been employed including: clinical and self breast exams, mammography, genetic screening, ultrasound, and magnetic resonance imaging.
  • a clinical or self breast exam involves feeling the breast for lumps or other abnormalities.
  • Research evidence does not support the effectiveness of either type of breast exam, because by the time a lump is large enough to be found it is likely to have been growing for several years and will soon be large enough to be found without an exam.
  • Mammographic screening for breast cancer uses x-rays to examine the breast for any uncharacteristic masses or lumps. In women at high risk, such as those with a strong family history of cancer, mammography screening is recommended at an earlier age and additional testing may include genetic screening that tests for the BRCA genes and/or magnetic resonance imaging.
  • Stage 1 cancers and DCIS have an excellent prognosis and are generally treated with lumpectomy with or without chemotherapy or radiation. Although the aggressive HER2+ cancers should also be treated with the trastuzumab (Herceptin) regime.
  • Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated with surgery (lumpectomy or mastectomy with or without lymph node removal), radiation (sometimes) and chemotherapy (plus trastuzumab for HER2+ cancers).
  • Stage 4 metastatic cancer, i.e., spread to distant sites is not curable and is managed by various combinations of all treatments from surgery, radiation, chemotherapy and targeted therapies. These treatments increase the median survival time of stage 4 breast cancer by about 6 months.
  • Ovarian cancer is a cancerous growth arising from different parts of the ovary. Most (>90%) ovarian cancers are classified as “epithelial” and were believed to arise from the surface (epithelium) of the ovary. However, recent evidence suggests that the Fallopian tube could also be the source of some ovarian cancers. Since the ovaries and tubes are closely related to each other, it is hypothesized that these cells can mimic ovarian cancer. Other types arise from the egg cells (germ cell tumor) or supporting cells (sex cord/stromal).
  • Ovarian cancer causes non-specific symptoms. Early diagnosis would result in better survival, on the assumption that stage I and II cancers progress to stage III and IV cancers (but this has not been proven). Most women with ovarian cancer report one or more symptoms such as abdominal pain or discomfort, an abdominal mass, bloating, back pain, urinary urgency, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding or involuntary weight loss. There can be a build-up of fluid (ascites) in the abdominal cavity.
  • Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test (for CA-125 and sometimes other markers), and transvaginal ultrasound.
  • the diagnosis must be confirmed with surgery to inspect the abdominal cavity, take biopsies (tissue samples for microscopic analysis) and look for cancer cells in the abdominal fluid.
  • Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy.
  • ovarian cancer In most cases, the cause of ovarian cancer remains unknown. Older women, and in those who have a first or second degree relative with the disease, have an increased risk. Hereditary forms of ovarian cancer can be caused by mutations in specific genes (most notably BRCA1 and BRCA2, but also in genes for hereditary nonpolyposis colorectal cancer). Infertile women and those with a condition called endometriosis, those who have never been pregnant and those who use postmenopausal estrogen replacement therapy are at increased risk. Use of combined oral contraceptive pills is a protective factor. The risk is also lower in women who have had their uterine tubes blocked surgically (tubal ligation).
  • Ovarian cancer is classified according to the histology of the tumor, obtained in a pathology report. Histology dictates many aspects of clinical treatment, management, and prognosis.
  • Surface epithelial-stromal tumour also known as ovarian epithelial carcinoma, is the most common type of ovarian cancer. It includes serous tumour, endometrioid tumor and mucinous cystadenocarcinoma. Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor and virilizing Sertoli-Leydig cell tumor or arrhenoblastoma, accounts for 8% of ovarian cancers.
  • the AJCC/TNM staging system includes three categories for ovarian cancer, T, N and M.
  • the T category contains three other subcategories, T1, T2 and T3, each of them being classified according to the place where the tumor has developed (in one or both ovaries, inside or outside the ovary).
  • the T1 category of ovarian cancer describes ovarian tumors that are confined to the ovaries, and which may affect one or both of them.
  • the sub-subcategory T1a is used to stage cancer that is found in only one ovary, which has left the capsule intact and which cannot be found in the fluid taken from the pelvis.
  • Stages T2b and T2c indicate cancer that metastasized to other pelvic tissues than the uterus and fallopian tubes and which cannot be seen in the fluid taken from the pelvis, respectively tumors that spread to any of the pelvic tissues (including uterus and fallopian tubes) but which can also be found in the fluid taken from the pelvis.
  • T3 is the stage used to describe cancer that has spread to the peritoneum. This stage provides information on the size of the metastatic tumors (tumors that are located in other areas of the body, but are caused by ovarian cancer). These tumors can be very small, visible only under the microscope (T3a), visible but not larger than 2 centimeters (T3b) and bigger than 2 centimeters (T3c).
  • This staging system also uses N categories to describe cancers that have or not spread to nearby lymph nodes. There are only two N categories, N0 which indicates that the cancerous tumors have not affected the lymph nodes, and N1 which indicates the involvement of lymph nodes close to the tumor.
  • the M categories in the AJCC/TNM staging system provide information on whether the ovarian cancer has metastasized to distant organs such as liver or lungs. M0 indicates that the cancer did not spread to distant organs and M1 category is used for cancer that has spread to other organs of the body.
  • the AJCC/TNM staging system also contains a Tx and a Nx sub-category which indicates that the extent of the tumor cannot be described because of insufficient data, respectively the involvement of the lymph nodes cannot be described because of the same reason.
  • Ovarian cancer as well as any other type of cancer, is also graded, apart from staged.
  • the histologic grade of a tumor measures how abnormal or malignant its cells look under the microscope. There are four grades indicating the likelihood of the cancer to spread and the higher the grade, the more likely for this to occur.
  • Grade 0 is used to describe non-invasive tumors.
  • Grade 0 cancers are also referred to as borderline tumors.
  • Grade 1 tumors have cells that are well differentiated (look very similar to the normal tissue) and are the ones with the best prognosis.
  • Grade 2 tumors are also called moderately well differentiated and they are made up by cells that resemble the normal tissue.
  • Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.
  • the signs and symptoms of ovarian cancer are most of the times absent, but when they exist they are nonspecific. In most cases, the symptoms persist for several months until the patient is diagnosed.
  • a strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), which confers a higher risk for developing ovarian cancer.
  • HNPCC hereditary nonpolyposis colorectal cancer
  • Patients with strong genetic risk for ovarian cancer may consider the use of prophylactic, i.e. preventative, oophorectomy after completion of childbearing.
  • Australia being member of International Cancer Genome Consortium is leading efforts to map ovarian cancer's complete genome.
  • a blood test called CA-125 is useful in differential diagnosis and in follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity. However, this is the only widely-used marker currently available.
  • a pelvic examination and imaging including CT scan and trans-vaginal ultrasound are essential. Physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or abdominal mass. The pelvic examination can include a rectovaginal component for better palpation of the ovaries. For very young patients, magnetic resonance imaging may be preferred to rectal and vaginal examination.
  • a surgical procedure to take a look into the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious areas will be removed and sent for microscopic analysis. Fluid from the abdominal cavity can also be analysed for cancerous cells. If there is cancer, this procedure can also determine its spread (which is a form of tumor staging).
  • Tubal ligation is believed to decrease the chance of developing ovarian cancer by up to 67% while a hysterectomy may reduce the risk of getting ovarian cancer by about one-third.
  • analgesics such as acetaminophen and aspirin seem to reduce one's risks of developing ovarian cancer. Yet, the information is not consistent and more research needs to be carried on this matter.
  • Routine screening of women for ovarian cancer is not recommended by any professional society—this includes the U.S. Preventive Services Task Force, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the National Comprehensive Cancer Network. This is because no trial has shown improved survival for women undergoing screening. Screening for any type of cancer must be accurate and reliable—it needs to accurately detect the disease and it must not give false positive results in people who do not have cancer. As yet there is no technique for ovarian screening that has been shown to fulfil these criteria. However, in some countries such as the UK, women who are likely to have an increased risk of ovarian cancer (for example if they have a family history of the disease) can be offered individual screening through their doctors, although this will not necessarily detect the disease at an early stage.
  • Surgical treatment may be sufficient for malignant tumors that are well-differentiated and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors that are confined to the ovary. For patients with advanced disease a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful.
  • Glioblastoma multiforme is the deadliest and most common form of malignant brain tumor. Even when aggressive multimodality therapy consisting of radiotherapy, chemotherapy, and surgical excision is used, median survival is only 12-17 months. Standard therapy for glioblastoma multiforme consists of maximal surgical resection of the tumor, followed by radiotherapy between two and four weeks after the surgical procedure to remove the cancer. This is followed by chemotherapy. Most patients with glioblastoma take a corticosteroid, typically dexamethasone, during their illness to palliate symptoms. Experimental treatments include gamma-knife radiosurgery, boron neutron capture therapy and gene transfer.
  • Oligodendroglioma is an incurable but slowly progressive malignant brain tumor. They can be treated with surgical resection, chemotherapy, and/or radiotherapy. For suspected low-grade oligodendrogliomas in select patients, some neuro-oncologists opt for a course of watchful waiting, with only symptomatic therapy. Tumors with the 1p/19q co-deletion have been found to be especially chemosensitive, and one source reports oligodendrogliomas to be among the most chemosensitive of human solid malignancies. A median survival of up to 16.7 years has been reported for low grade oligodendrogliomas.
  • the diagnosis will often start with an interrogation of the patient to get a clear view of his medical antecedents, and his current symptoms.
  • Clinical and laboratory investigations will serve to exclude infections as the cause of the symptoms.
  • Examinations in this stage may include ophtamological, otolaryngological (or ENT) and/or electrophysiological exams.
  • EEG electroencephalography
  • Benign brain tumors often show up as hypodense (darker than brain tissue) mass lesions on cranial CT-scans. On MRI, they appear either hypo- (darker than brain tissue) or isointense (same intensity as brain tissue) on T1-weighted scans, or hyperintense (brighter than brain tissue) on T2-weighted MRI, although the appearance is variable.
  • meningiomas with the exception of some tumors located at the skull base, can be successfully removed surgically.
  • Most pituitary adenomas can be removed surgically, often using a minimally invasive approach through the nasal cavity and skull base (trans-nasal, trans-sphenoidal approach).
  • Large pituitary adenomas require a craniotomy (opening of the skull) for their removal.
  • Radiotherapy including stereotactic approaches, is reserved for inoperable cases.
  • Radiotherapy is integral parts of the therapeutic standard for malignant tumors. Radiotherapy may also be administered in cases of “low-grade” gliomas, when a significant tumor burden reduction could not be achieved surgically.
  • Seizures can vary from absences to severe tonic-clonic attacks. Medication is prescribed and administered to minimize or eliminate the occurrence of seizures.
  • the goal of radiation therapy is to selectively kill tumor cells while leaving normal brain tissue unharmed.
  • standard external beam radiation therapy multiple treatments of standard-dose “fractions” of radiation are applied to the brain. This process is repeated for a total of 10 to 30 treatments, depending on the type of tumor. This additional treatment provides some patients with improved outcomes and longer survival rates.
  • Radiosurgery is a treatment method that uses computerized calculations to focus radiation at the site of the tumor while minimizing the radiation dose to the surrounding brain. Radiosurgery may be an adjunct to other treatments, or it may represent the primary treatment technique for some tumors.
  • Radiotherapy may be used following, or in some cases in place of, resection of the tumor.
  • Forms of radiotherapy used for brain cancer include external beam radiation therapy, brachytherapy, and in more difficult cases, stereotactic radiosurgery, such as Gamma knife, Cyberknife or Novalis Tx radiosurgery.
  • Radiotherapy is the most common treatment for secondary brain tumors.
  • the amount of radiotherapy depends on the size of the area of the brain affected by cancer.
  • Conventional external beam ‘whole brain radiotherapy treatment’ (WBRT) or ‘whole brain irradiation’ may be suggested if there is a risk that other secondary tumors will develop in the future.
  • Stereotactic radiotherapy is usually recommended in cases involving fewer than three small secondary brain tumors.
  • Radiotherapy is often used in young children instead of radiation, as radiation may have negative effects on the developing brain.
  • the decision to prescribe this treatment is based on a patient's overall health, type of tumor, and extent of the cancer. The toxicity and many side effects of the drugs, and the uncertain outcome of chemotherapy in brain tumors puts this treatment further down the line of treatment options with surgery and radiation therapy preferred.
  • a shunt is used not as a cure but to relieve symptoms by reducing hydrocephalus caused by blockage of cerebrospinal fluid.
  • the present oligo-benzamide analogs are extremely potent and effective on various cancer cells including breast cancer, ovarian cancer, and pancreatic cancer. These compounds have a unique mode of action compared to existing therapeutic treatments to these diseases.
  • the compounds are very potent with IC 50 values of 10-50 nM for growth inhibition.
  • TK41 is a tris-benzamide analog and it inhibits nuclear receptor (NR) interaction with its coregulator proteins in cancer cells with high potency (IC 50 is approximately 100 nM; FIGS. 1 - 4 ). This compound was found to be very effective on endocrine therapy resistant breast cancer cells that are difficult to be treated by currently available endocrine and chemotherapy ( FIG. 2 and FIG. 8 ).
  • TK41 was initially designed to target the estrogen receptor, it was found to also exhibit activity in triple negative breast cancer cells that are estrogen-receptor negative ( FIG. 2 and FIGS. 5 - 7 ). This result was unexpected based on the performance of earlier benzamide compounds (see FIG. 9 for structure activity table). Indeed, TK41 shows remarkably strong growth inhibition of triple-negative breast cancer cells (TNBC) with the IC50 values below 100 nM. TNBC is difficult to be treated and currently there are no good drugs available in the market. Animal studies with TK41 not only showed outstanding tumor growth inhibition but also showed no apparent side effects or toxicity. TK41 is orally available and an excellent therapeutic candidate for a broad range of breast cancers.
  • TNBC triple-negative breast cancer cells
  • TK208 was synthesized and tested against breast cancer and ovarian cancer cell lines ( FIGS. 10 - 15 ).
  • TK208 showed remarkably high potency in growth inhibition of TNBC and ovarian cancer cells with IC50 values from 10-100 nM.
  • These compounds e.g., TK41, TK208, TK308 ( FIG. 21 ), TK309 ( FIG. 22 ), TK314, TK315) are extremely potent compounds that inhibit tumor growth and kill breast and ovarian cancer cells and as such, they are superb therapeutic candidates for such diseases.
  • Tris-benzamide YL144 was also synthesized and was found to inhibit vitamin D receptor (VDR) with high potency and may be a useful therapeutic candidate for pancreatic cancer ( FIGS. 16 - 18 ).
  • Bis-benzamide TK245 is a unique compound showing strong growth inhibition of estrogen receptor-positive breast cancer ( FIG. 19 and FIG. 20 ).
  • Endoplasmic reticulum stress was also induced in pancreatic cancer MiaPaca cells upon exposure to TK41 but does not induce endoplasmic reticulum stress in HMEC cells ( FIG. 29 ).
  • the mechanism of action of TK41 may operate comprise targeting either ER or TLX and inducing endoplasmic reticulum stress, subsequent apoptosis, and blocking autophagic fusion ( FIG. 30 ).
  • AM PS resin (0.42 mmol/g, 3.0 g, 1.26 mmol) was swollen in DMF for 12 h and washed with DMF (3 ⁇ 1 min).
  • a solution of BAL linker (676 mg, 2.52 mmol), PyBOP (1.44 g, 2.77 mmol) and DIEA (0.97 mL, 5.6 mmol) in DMF (25 mL) was added to the resin, shaken at room temperature for 24 h, and washed with DMF (3 ⁇ 1 min). The completion of the coupling reaction was confirmed by a negative Kaiser ninhydrin test.
  • Compound 2 A mixture of compound 1 (0.25 g, 0.11 mmol), naphthalene-2-methaneamine hydrochloride (85 mg, 0.44 mmol), NaBH 3 CN (29 mg, 0.44 mmol) in 1% AcOH/DMF (5 mL) was shaken at room temperature for 24 h, and washed with DMF (3 ⁇ 1 min). The reaction was monitored using a positive chloranil test.
  • Compound 8 This compound was prepared from compound 7 by using the same procedure as that for compound 4.
  • TK296 A mixture of compound 9 in 5% H 2 O/TFA (5 mL) was shaken at room temperature for 2 h, and then the TFA solution was filtered, and the resin was washed with TFA (2 mL) and DCM (2 mL). The combined TFA solution was concentrated with a gentle stream of nitrogen, and a white solid was precipitated by adding cold diethyl ether (5 mL). The white solid was washed with ether and dried in vacuo to give TK296 (30 mg, 28%)
  • TK207 A solution of compound 8 (40 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIEA (27 ⁇ L, 0.16 mmol) in DMF (3 mL) was stirred at room temperature for 1 h. 7-Amino-1H-indazole (20 mg, 0.15 mmol) was then added to the reaction mixture and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (30 mL) and 1 N HCl (20 mL). The organic layer was separated and washed with 1 N HCl (20 mL) and brine (20 mL). The organic layer was concentrated under reduced pressure to yield the crude product. Purification by crystallization from EtOAc gave compound 9 as a yellow solid.
  • TK315 A solution of compound 1 (50 mg, 0.078 mmol), HATU (39 mg, 0.10 mmol), DIEA (41 ⁇ L, 0.24 mmol) in DMF (4 mL) was stirred at room temperature for 1 h, and then compound 2 (91 mg, 0.24 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 24 h and then diluted with EtOAc (20 mL) and 1 N HCl (10 mL). The organic layer was separated, washed with 1 N HCl (10 mL) and brine (10 mL), and concentrated under reduced pressure. The resulting solid was washed with EtOAc and dried in vacuo to give compound 3 as a yellow sold.
  • YL144 A mixture of compound 1 (0.20 g, 0.30 mmol), 2-aminoimidazole sulfate (79 mg, 0.60 mmol) and DIEA (0.42 mL, 2.4 mmol) in DMF (20 mL) was stirred at 60° C. for 1 h. HATU (0.15 g, 0.39 mmol) was then added to the reaction mixture and the resulting mixture was stirred at 60° C. for 24 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and 1 N HCl (30 mL). The organic layer was separated and washed with 1 N HCl (30 mL) and brine (30 mL). The organic layer was concentrated under reduced pressure to yield the crude product. Purification by crystallization from EtOAc gave compound 2 as a yellow solid.
  • the inventors have conducted several studies at UTHSCSA using preclinical murine Xenograft and Patient derived xenografts (PDX) examining the efficacy of new compounds TK41 (ERX-41), TK208 (ERX-208) and TK315 (ERX-315). The results are given below.
  • TK315 (ERX-315) in captisol formulation showed potent activity against both MCF7-MT ESR1 ZR-75 and ZR75-MT Y537S ER ⁇ expressing therapy resistant BC xenograft models but no effect on mouse liver or body weight ( FIGS. 31 A-C ). Histologic evaluation of the tumors showed dramatically decreased Ki67 proliferation indices in these tumors. Importantly, the lack of immune antibody infiltrates in the spleen, lymph nodes, kidney, or liver of the syngeneic D2A1 tumors with treated with ERX-315 suggested that ERX-315 is potent, not immunogenic and can be safely administered orally.
  • PDX models recapitulate the structural complexity and individual heterogeneity of human BC (primary tumor samples), therefore, studies with these models will establish an incontrovertible basis for clinical translation.
  • Three different TNBC PDX tumors were established in NSG mice by transplanting PDX tumor pieces into the mammary fat fad using established protocol in the inventors' lab. Results showed that TK41 (ERX-41) treatment significantly decreased the growth of all the three TNBC PDX tumors tested ( FIGS. 32 A-C ).
  • TK208 ERX-208
  • results showed that TK208 (ERX-208) has good efficacy in reducing the ovarian tumor volume with no effect on mouse body weight, suggesting lack of toxicity ( FIGS. 33 A-H ).
  • ERX-41 has potent activity against TNBC cells in vitro. To evaluate the generalizability of the inventors' findings, they evaluated ERX-41 in a large number of TNBC and ERa-positive cell lines. In 22 human preclinical TNBC cell line models, representing all six molecular subtypes of TNBC, ERX-41 had potent antiproliferative activity with an IC 50 ⁇ 500 nM using WST assays and ⁇ 250 nM using CellTiter-Glo cell viability assays ( FIGS. 34 A-B ).
  • ERX-41 did not have significant effect against normal human mammary epithelial cells (HMEC) at >1 ⁇ M with either the WST, MTT or CellTiter-Glo assays ( FIGS. 34 A-B ). Live cell imaging studies indicated that ERX-41 significantly induced cell death in TNBC cells within 30 hours of treatment in a vast majority of the cells (>90%) compared to control ( ⁇ 1%). By contrast, ERX-41 did not significantly induce cell death in HMEC cells.
  • ERX-41 has potent activity against TNBC in vivo.
  • Daily oral or intraperitoneal administration of ERX-41 up to 200 mg/kg doses were well tolerated by mice, with no clear evidence of toxicity.
  • ERX-41 decreased tumor growth, as shown by extirpated tumor sizes at the end of study ( FIG. 35 C and FIG. 35 E ). Importantly, ERX-41 treatment did not show overt signs of toxicity, as evidenced by no alterations in mouse body weights in the treated mice ( FIG. 35 D ). Further, ERX-41 was able to significantly reduce the growth of D2A1 xenografts in a syngeneic tumor model ( FIGS. 35 F-H ). The inventors validated the activity of ERX-41 in four distinct TNBC PDXs established in the mammary fat pad ( FIGS. 35 I-P ).
  • xenografts of SUM-159 with LIPA KO did not respond to oral administration of ERX-41, in contrast to parental SUM-159 xenografts which responded significantly to ERX-41 in vivo ( FIGS. 37 I-J ).
  • ERX-41 has activity on human TNBC tumors. To ascertain that ERX-41 would have activity against primary TNBC tumors, the inventors leveraged their prior significant experience with the ex vivo patient derived explant (PDE) cultures ( FIG. 38 A ). The PDE cultures, maintains the native tissue architecture and better recapitulates the heterogeneity of human TNBC in a laboratory setting. The inventors have noted that ERX-41 had significant activity, as evidenced by decreased proliferation (ki67 staining) and increased apoptosis (cleaved caspase 3 staining) of TNBC PDEs ( FIGS. 38 C-D ).
  • LIPA has a single 239LXXLL243 (SEQ ID NO: 1) motif and that ERX-41 (shown in green, FIGS. 39 A-E ) could potentially interact with this LXXLL (SEQ ID NO: 1) motif which was noted to be in the lid region of LAL (LXXLL (SEQ ID NO: 1) motif shown in orange, FIGS. 39 A-E ).
  • LXXLL LXXLL
  • FIGS. 39 A-E the critical domain of lipase activity of LIPA appeared to be spatially distinct from the LXXLL (SEQ ID NO: previous studies have identified a LIPA point mutation H 274 Y in LAL helix 13, that is known to abrogate LIPA lipase function ( FIG. 39 F ).
  • LIPA plasmid constructs under a constitutive promoter including wild type LIPA (WT-LIPA), H 274 Y mutant LIPA (H 274 Y MT-LIPA), DLXXLL (SEQ ID NO: 2) mutant LIPA (deletion of the 238NLCFLLC244 cap), and the L242P mutant LIPA (point mutation of the second L in the LXXLL (SEQ ID NO: 1) motif).
  • ERX-208 causes growth inhibition of OCa cells, as noted by MTT assays using five established OCa cells (ES2, SKOV3, A2780, TOV21G, TOV112D) and five primary OCa cells derived from HGSOC patient ascites (AS21, AS23, AS25, AS28, AS29) ( FIGS. 42 B-C ).
  • ERX-11 has limited activity against OCa cells ( FIG. 42 A ).
  • ERX-208 has limited activity in normal ovarian surface epithelial cells (IOSE) ( FIG. 42 D ).
  • ERX-208 treatment reduced colony formation ( FIG. 43 ) and invasion ( FIG. 11 , using BD Biocoat Matrigel invasion assays) of SKOV3 and ES2 OCa cells.
  • results using Caspase-Glo® 3/7 Assay showed that ERX-208 promotes apoptosis of OCa cells ( FIG. 40 ).
  • these data indicate that ERX-208 can induce ERS in OCa cells, reduce growth and induce apoptosis in OCa cells.
  • ERX-208 is effective in reducing growth of chemotherapy resistant OCa. OCa initially responds to chemotherapy; however, majority will develop chemotherapy resistance. ERX-208 significantly reduced viability of carboplatin resistant OCa cells and promoted apoptosis ( FIGS. 49 A-B ).
  • the inventors conducted a proof of principle study using a therapy resistant HGSOC PDX model received from the UTHealth OBGYN PDX core. ERX-208 treatment resulted ⁇ 60% reduction in tumor volume ( FIGS. 49 C-F ). IHC analyses showed increased activation of ERS markers such as GRP78, p-PERK and decreased proliferation measured by Ki67 ( FIG. 50 )
  • TX-542 structure and modeled fitting for WT-ER ⁇ and MT-ER ⁇ shown in FIG. 51 .
  • TX-542 was potent (IC 50 ⁇ 20-50 nM) as an antiproliferative agent against expressing MT-ER ⁇ , both in genetically modified MCF-7 cells with one WT-ER ⁇ allele and one MT-ER ⁇ allele introduced by CRISPR and genetically modified ZR-75 or T47-D cells in which both copies of WT-ER ⁇ alleles were replaced using CRISPR with MT-ER ⁇ .
  • TX-542 had no activity against ER-null (SUM-159 or MDA-MB-231 cells) or non-tumorigenic breast epithelial cells, such as human mammary epithelial cells (HMEC). While several orally available SERDs (GDC-0810, AZD-9496) have shown some preclinical utility in treating ETR-BC tumors (Lai et al., 2015; Weir et al., 2016), their clinical development has been halted because of limitations with efficacy, bioavailability and toxicity. In addition, these agents are not able to consistently target all the MT-ER ⁇ forms in distinct genetic contexts, as shown in FIG. 52 and as reported by others.
  • the inventors did find potent activity of these drugs against some cell lines expressing MT-ER ⁇ (for example, AZD-9496 aginst the T47-D Y537S MT) but not against others expressing the same mutation (AZD-9496 against the ZR-75 or MCF-7 Y537S MT).
  • the inventors noted that only TX-542 had a consistent and potent activity effect against MT-ER ⁇ , with IC 50 ⁇ 50 nM in multiple models, including those with expression of MT-ER ⁇ alone (ZR-75 and T47-D) on in conjunction with the WT-ERa (MCF-7) ( FIG. 53 ).
  • TX-542 significantly reduced the survival of BC cells expressing WT-ER ⁇ and MT-ER ⁇ ( FIG. 54 ). While TX-542 potently reduced soft agar colony formation in MCF-7 MT-ER Y537S cells ( FIG. 54 ), neither the parental ERX-11, tamoxifen nor GDC0810 SERD (at the same concentrations) had an effect on colony formation.
  • TX-542 (10 mg/kg/ip) showed potent activity against growth of established WT-ER ⁇ ZR-75 or MT-ER ⁇ MCF-7 xenografts, but had no effect on mouse body weights ( FIG. 59 ).
  • TX-542 functions like a slow-acting SERD and causes decreased ER ⁇ protein levels over time ( FIG. 60 ). However, unlike fulvestrant, the kinetics of TX-542 mediated downregulation of ER ⁇ are much slower: fulvestrant causes WT-ER ⁇ degradation within 4 h, while the effect of TX-542 on MT-ER ⁇ levels is not noticeable until 24 h and more pronounced at 48 h. These data suggest that TX-542 causes decreased MT-ERa protein levels by blocking the MT-ER ⁇ -regulated transcriptional program, which includes auto-regulation of ERa gene expression.
  • RNA-sequencing data suggests that TX-542 dramatically alters the transcription of ER ⁇ -regulated genes, with repression of canonical estradiol-upregulated and induction of estradiol-repressed genes ( FIG. 61 A-D ).
  • the ability of TX-542 to influence MT-ER ⁇ genomic signaling was validated by reporter gene assays, which indicate that TX-542 was able to decrease transcription driven by a minimal promoter with three copies of the ER-response element (ERE) ( FIG. 61 E ) and by chromatin immunoprecipation (ChIP) studies which show that TX-542 blocks both basal and estradiol-induced MT-ER ⁇ DNA binding ( FIGS.
  • TX-542 potently affects the invasion of multiple BC cells expressing MT-ER ⁇ ( FIG. 62 ). Since MT-ER ⁇ is primarily expressed in metastases, the inventors used metastatic models to evaluate effect of TX-542 on the development and progression of metastasis. These studies showed that TX-542 could both dramatically decrease the formation of lung metastasis when started immediately after intracardiac injection (1/6 tumors treated with TX-542 formed mets within 4 weeks while 6/6 treated with vehicle had mets and had to be euthanized) ( FIG.
  • ERX-315 The binding of ERX-315 (structure shown in FIG. 65 C ) to ER ⁇ has been validated for WT ER ⁇ LBD using time-resolved FRET (TR-FRET)-ER ⁇ Coactivator assay ( FIG. 65 D : purified MT-ER ⁇ LBD is not available).
  • TR-FRET time-resolved FRET
  • ERX-315 had no activity against benign breast epithelial cells, shown for the human mammary epithelial cells (HMEC). In contrast, ERX-314 has dramatically lower potency (IC 50 ⁇ 1500-5000 nM) and serves an internal control for ERX-315. The inventors have performed most of the studies described below with three compounds-ERX-315 as the optimized lead, ERX-11 as the parental compound and ERX-314 as a negative control.
  • ERX-315 was orally bioavailable in captisol formulation with half life in plasma ⁇ 4.5 hours (Table 3). At 24 h after oral administration, ERX-315 was still detectable in the plasma at >500 ng/mL. Importantly, evaluation of MCF-7 tumor xenograft tissue showed that after 2 weeks of daily oral dosing of 10 mg/kg ERX-315, ERX-315 levels reached a steady state and remained detectable at >0.1 ⁇ g/g tissue levels even 16 h after the last dose, correlating with >100 nM ERX-315, which is above the therapeutic dose of ERX-315.
  • mice with orthotopic MCF7 xenograft tumors were treated with 10 mg/kh ERX-315 dosed orally 5 days/week for 10 days. Tumors were harvested 2, 4, 8 and 16 h after last dose, and snap frozen. Drug concentrations in the blood and tumor were determined following extraction with acetronitrile by HPLC/MS. A standard curve was generated for both blood and tumor by spiking known concentrations of the drug prior to evaluation by HPLC.

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